Francois Vigneault (Shape Therapeutics)

EX­CLU­SIVE: Shape Ther­a­peu­tics rais­es $112M in bid to make RNA edit­ing — and a whole lot else — a re­al­i­ty

Two years af­ter spin­ning out of CRISPR pi­o­neer Prashant Mali’s lab, Shape Ther­a­peu­tics has a lot more cash and a slight­ly new mis­sion.

The com­pa­ny orig­i­nal­ly launched in 2019 with plans to de­vel­op ther­a­pies around a new form of gene edit­ing, one they hoped could bet­ter ad­dress cer­tain dis­eases than CRISPR or oth­er forms of gene ma­nip­u­la­tions. That’s still their goal, but CEO Fran­cois Vi­gneault has added a few oth­ers in the mean­time.

“The com­pa­ny re­al­ly start­ed as, how can we find a so­lu­tion to some of the lim­i­ta­tions of gene edit­ing?” Vi­gneault said. “But from there, we quick­ly re­al­ized there was a mas­sive bot­tle­neck in an­oth­er sphere of gene ther­a­py.”

Shape end­ed up spend­ing con­sid­er­able time and re­sources try­ing to de­vel­op and make broad­ly avail­able so­lu­tions to two of the biggest con­straints that have held up the broad­er field: man­u­fac­tur­ing and de­liv­ery. They’ll now have a lot more mon­ey to do so and bring for­ward their own med­i­cines, an­nounc­ing a $112 mil­lion Se­ries B on Thurs­day led by Decheng Cap­i­tal and Bre­ton Cap­i­tal.

Shape spe­cial­izes in RNA edit­ing; the com­pa­ny tries to de­vel­op ther­a­pies that in­ter­cept the bro­ken mes­sages that the DNA of pa­tients with cer­tain dis­eases sends out and cor­rect it be­fore it gets turned in­to pro­teins. That con­trasts with CRISPR and oth­er gene edit­ing ap­proach­es that try to di­rect­ly — and per­ma­nent­ly – al­ter DNA.

It does so by ex­ploit­ing a nat­u­ral­ly oc­cur­ring en­zyme that’s al­ready present in hu­man cells called ADAR. By send­ing in their own spe­cial­ly con­struct­ed strand of guide RNA, re­searchers can in the­o­ry re­cruit this en­zyme and get it to ma­nip­u­late spe­cif­ic strands of mes­sen­ger RNA in par­tic­u­lar ways. They could, for ex­am­ple, delete or add bases.

Shape is fo­cus­ing their ef­forts on neu­rons, where ADAR seems to work par­tic­u­lar­ly well — pos­si­bly be­cause it’s nat­u­ral­ly high­ly ex­pressed — and where, by con­trast, CRISPR com­pa­nies have had par­tic­u­lar dif­fi­cul­ty ap­ply­ing their more well-known tech­nol­o­gy. They have lead pro­grams in the rare ge­net­ic dis­ease Rett syn­drome and Parkin­son’s.

In de­vel­op­ing those ther­a­pies, Vi­gneault and his col­leagues ran square in­to the prob­lems every gene ther­a­py com­pa­ny has hit dur­ing the field’s 2010s resur­gence. The vi­ral vec­tors used to shut­tle genes (or in this case, RNA) are dif­fi­cult to man­u­fac­ture at scale. And it’s dif­fi­cult to de­vel­op ones that go pre­cise­ly to the right tis­sue and the right kind of cell in hu­mans.

“We found this [tech­nol­o­gy] is a ma­jor ad­van­tage in neu­rons and CNS dis­or­ders,” Vi­gneault said. “But on the de­liv­ery front what we dis­cov­er is a huge lim­i­ta­tion.”

So Shape en­gi­neered a cell line they claim can pro­duce more ade­no-as­so­ci­at­ed virus (AAV), the most com­mon vi­ral vec­tor used in gene ther­a­py, than any oth­er method. And they in­vest­ed in the tech­nol­o­gy to en­gi­neer AAVs, screen­ing mil­lions of AAVs in cells and mon­keys to de­vel­op ones par­tic­u­lar­ly suit­ed to reach­ing neu­rons or mus­cles.

That puts Shape in di­rect com­pe­ti­tion with com­pa­nies such as Affinia and Dyno, which are ded­i­cat­ed sole­ly to AAV en­gi­neer­ing and have raised hun­dreds of mil­lions of dol­lars and signed bil­lion-dol­lar deals with Big Phar­ma for their vec­tors.

Vi­gneault said Shape will sim­i­lar­ly try to make their AAV and cell lines avail­able to oth­er groups in in­dus­try and acad­e­mia, while con­tin­u­ing to de­vel­op their own ther­a­pies in house and with larg­er com­pa­nies. They have broad am­bi­tions there, too, re­cent­ly up­dat­ing their “pipeline” on­line to show, rather than the few pro­grams clos­est to the clin­ic, a con­stel­la­tion of the dozens of dis­eases they be­lieve their ADAR tech is best suit­ed for, from Alzheimer’s to cys­tic fi­bro­sis.

“The idea is to build a slight­ly dif­fer­ent com­pa­ny than the typ­i­cal one,” Vi­gneault said. “First make a tool that’s dis­rup­tive, not an in­cre­men­tal im­prove­ment, and when you have that tool, make it avail­able so that you can help as many pa­tients as pos­si­ble be­cause one com­pa­ny can’t do it all.”

Cor­rec­tion: The ar­ti­cle has been to clar­i­fy Shape spun out of the Mali lab, not the Church lab.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Clay Siegall, Morphimmune CEO

Up­dat­ed: Ex-Seagen chief Clay Sie­gall emerges as CEO of pri­vate biotech

Clay Siegall will be back in the CEO seat, taking the helm of a private startup working on targeted cancer therapies.

It’s been almost a year since Siegall resigned from Seagen, the biotech he co-founded and led for more than 20 years, in the wake of domestic violence allegations by his then-wife. His eventual successor, David Epstein, sold the company to Pfizer in a $43 billion deal unveiled last week.

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Zhi Hong, Brii Biosciences CEO

Brii Bio­sciences stops man­u­fac­tur­ing Covid-19 an­ti­body com­bo, plans to with­draw EUA re­quest

Brii Biosciences said it will stop manufacturing its Covid-19 antibody combination, sold in China, and is working to withdraw its emergency use authorization request in the US, which it started in October 2021.

The Beijing and North Carolina biotech commercially launched the treatment in China last July but is now axing the work and reverting resources to other “high-priority programs,” per a Friday update. The focus now is namely hepatitis B viral infection, postpartum depression and major depressive disorders.

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FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

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Sergio Traversa, Relmada Therapeutics CEO

Rel­ma­da makes 'crit­i­cal changes' to PhI­II tri­al to try and save de­pres­sion drug

Relmada Therapeutics is making changes to its Phase III study of its lead drug for major depressive disorder, in an attempt to avoid problems with a prior trial that showed little difference between the drug and a placebo.

That failure in October wiped 80% from Relmada’s stock price, and was followed by another negative readout a few months later. In both cases, the company said that there had been trial sites that were associated with what it called surprising placebo effects that skewed the results compared with the drug, REL-1017.

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Paul Song, NKGen Biotech CEO

NK cell ther­a­py-fo­cused biotech eyes SPAC deal

A small, Santa Ana-based biotech created in 2017 is looking to enter a SPAC deal as it lays out plans to begin trials in its lead cell therapy candidates and bring on new executives.

Graf Acquisition Corp. IV and NKGen Biotech announced Thursday, with few other details, that the two companies signed a non-binding letter of intent to “pursue a business combination.” Graf Acquisition II and III withdrew their IPOs last year.

In­cyte hit by CRL on ex­tend­ed-re­lease JAK tablets, mud­dy­ing plans for Jakafi fran­chise ex­pan­sion

The FDA has rejected Incyte’s extended-release formulation of ruxolitinib tablets, in a surprise setback for the company’s plans to build on its blockbuster Jakafi franchise.

The ruxolitinib XR tablets are designed to be taken once a day, whereas Jakafi is indicated for twice daily dosage (although some patients can take it once daily).

According to Incyte, the FDA acknowledged in its complete response letter that the study submitted in the NDA “met its objective of bioequivalence based on area under the curve (AUC) parameters but identified additional requirements for approval.”

Peter Hecht, Cyclerion Therapeutics CEO

Hard pressed for cash, Cy­cle­ri­on looks for help fund­ing rare dis­ease drug

Cyclerion Therapeutics may have the design of a Phase IIb study ready to go, but it’s scrambling for a way to fund it.

The company said in a press release that it’s “actively evaluating the best combination of capital, capabilities, and transactions available to it to advance the development of zagociguat,” its lead candidate for a rare, genetic mitochondrial disease known as MELAS.

In a separate SEC filing, Cyclerion once again flagged “substantial doubt about (its) ability to continue as a going concern.” As of the end of 2022, it had cash and cash equivalents of only $13.4 million.

Three­'s a crowd as an­oth­er Kite ex­ec hits the ex­it; Surf­ing tough wa­ters, Celyad On­col­o­gy picks up new CEO

Kite Pharma is losing another exec, as Francesco Marincola leaves his post to join Flagship startup Sonata Therapeutics as CSO. Marincola served as Kite’s SVP and global head of cell therapy research, having joined the company in 2021 after a stint as CSO at Refuge Biotechnologies. Marincola has also served as a distinguished research fellow at AbbVie and spent more than two decades at the NIH and NCI. Marincola’s exit from Kite marks the third, following CEO Christi Shaw and Tecartus global program clinical lead Behzad Kharabi, who both left last month.

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